ES2349647T3 - MICROEMULSION FORMULATIONS THAT INCLUDE PARTICULAR SUBSTANCE ANTAGONISTS. - Google Patents

Abstract

The present invention relates to dispersible pharmaceutical compositions in which the active agent is a substance P antagonist, in particular a 5-aryl-4(R)-arylcarbonylamino-pent-2-enoic acid amide, that is useful for the treatment and prevention of respiratory diseases including asthma and chronic obstructive pulmonary disease, bowel disorders including irritable bowel syndrome (IBS), urinary incontinence, and cough.

Description

[0001] The present invention relates to novel pharmaceutical compositions in which the active agent is an antagonist of substance P, in particular a 5-aryl-4 (R) arylcarbonylamino-pent-2-enoic acid amide, which is useful for the treatment and prevention of respiratory diseases that include asthma and chronic obstructive pulmonary disease, bowel disorders that include irritable bowel syndrome (IBS), urinary incontinence, and cough.

[0002] They are known from Gerspacher et al. (Bioorg. Med. Chem. Lett. 2001; 11: 3081-3084), two dual neuroquinine antagonists NK (1) / NK (2), namely N - [(R, R) - (E) -1- arylmethyl-3- (2-oxo-azepan3-yl) carbamoyl] allyl-N-methyl-3,5-bis (trifluoromethyl) benzamides and 3- [N'-3,5-bis (trifluoromethyl) benzoylN-arylmethyl-N '-methylhydrazino] -N - [(R) -2-oxoazepan-3-yl] propionamides.

[0003] M. Zabka (Farmaceuticky Obzor 2003 Slovakia; 72: 97-92) describes colloidal drug delivery systems and microemulsions as drug delivery vehicles.

[0004] D. J. Hauss describes lipid-based systems for oral drug delivery and in particular the improvement of the bioavailability of poorly water soluble drugs (American Pharmaceutical Review 2002; 5: 22-28).

[0005] The 5-aryl-4 (R) -arylcarbonylamino-pent2-enoic acid amide substance P antagonists are a class of compounds described in international patent application WO 98/07694.

[0006] The 5-aryl-4 (R) -arylcarbonylamino-pent2-enoic acid amide substance P antagonists, such as those described in WO 98/07694, present highly specific difficulties in relation generally to administration and in particularly with galenic compositions, which include in particular problems of drug bioavailability and variability in response to intra-and intra-patient doses, which need the development of an unconventional dosage form.

[0007] In accordance with the present invention, it has now been surprisingly found that stable pharmaceutical compositions can be obtained with the 5-aryl-4 (R) -arylcarbonylamino-pent-2-enoic acid amide substance antagonists. which have particularly interesting bioavailability characteristics and reduce the variability in inter-and intra-subject bioavailability parameters. It has been found that these novel compositions attend or substantially reduce the difficulties encountered previously. It has been shown that the compositions of the invention allow effective dosing with concomitant improvement of bioavailability as well as reduced variability of absorption / bioavailability levels for and between individual patients. Thus, the invention can achieve elective therapy with tolerable dosage levels of such 5-aryl-4 (R) -arylcarbonylamino-pent-2-enoic acid P-substance antagonists, and may allow for more closed standardization and optimization of The daily dosage requirements for each individual.

[0008] Consequently, the occurrence of potential unwanted side effects is reduced and the overall cost of therapy can be reduced.

[0009] In a first aspect the present invention provides a spontaneously dispersible pharmaceutical composition comprising a 5-aryl-4 (R) -arylcarbonylamino-pent-2-enoic acid amide substance P antagonist and a carrier medium comprising a lipophilic component and a surfactant.

[0010] The spontaneously dispersible pharmaceutical composition is also referred to herein as a "composition of the invention". A pre-concentrated microemulsion is preferable.

2 [0011] The terms used in the specification have the following meanings: "Active agent" as used herein means a 5-aryl-4 (R) -arylcarbonylamino-pent-2-enoic acid amide substance P antagonist, such as that described in WO 98/07694. "Poorly soluble in water" as used herein means that it has a solubility in water at 20 ° C of less than 1%, for example 0.01% weight / volume, ie a "sparingly soluble to slightly soluble drug" as described in Remington: The Science and Practice of Pharmacy, 19 Edition, Ed. AR Gennaro, Mack Publishing Company, US, 1995, vol. 1, p 195. "Bioavailable" as used herein with reference to a composition means that the composition provides a maximum concentration of the active agent in that composition in an environment of use that is at least 1.5 times that of a control comprising an equivalent amount of the non-dispersed drug. "Spontaneously dispersible pharmaceutical composition" as used herein means a composition that contains an active agent defined herein and is capable of producing colloidal structures when diluted with an aqueous medium, for example water, or in gastric juices. The colloidal structures may be solid or preferably liquid particles that include drops and nanoparticles. The spontaneously dispersible pharmaceutical composition is preferably a microemulsion preconcentrate. "Microemulsion preconcentrate" as used herein means a composition that spontaneously forms a microemulsion in an aqueous medium, for example, in water, for example in dilution of 1: 1 to 1: 300, preferably 1: 1 to 1:70, but especially 1: 1 a

1:10 or in gastric juices after oral application.

"Microemulsion" as used herein means a non-opaque colloidal dispersion or

substantially non-opaque, opalescent or slightly opaque that forms spontaneously or

substantially spontaneously when its components come into contact with a

aqueous medium. A microemulsion is thermodynamically stable and typically contains

dispersed drops of an average diameter of less than about 200 nm (2000 A).

Generally the microemulsions comprise drops or liquid nanoparticles that have a

mean diameter of less than about 150 nm (1500 A); typically less than 100

nm, generally more than 10 nm, and are stable for periods of up to 24 hours.

[0012] Microemulsions offer greater ease of preparation due to spontaneous formation, thermodynamic stability, transparent and elegant appearance, increased drug loading, random penetration through biological membranes, increased bioavailability, and less inter-and intra-individual variability in Drug pharmacokinetics than rough emulsions.

[0013] Additional features can be found in the UK patent specification GB 2,222,770; Rosof, Progress in Surface and Membrane Science, 12, 405 et seq. Academic Press (1975); Friberg, Dispersion Science and Technology, 6 (3), 317 et scq. (1985); and Muller et al. Pharm Ind., 50 (3), 370 et seq. (1988)].

[0014] Through this specification and in the claims that follow, unless the context requires otherwise, the word "comprises", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a fixed integer or stage or group of integers or stages but not the exclusion of any other integer or stage or group of integers or stages.

[0015] In a second aspect the present invention provides a spontaneously dispersible pharmaceutical composition comprising a 5-aryl-4 (R) -arylcarbonylamino-pent-2-enoic acid amide substance P antagonist as an active agent, and a carrier medium comprising a lipophilic component, a surfactant, and additionally a hydrophilic component.

[0016] Preferably the spontaneously dispersible pharmaceutical composition is suitable for oral administration.

[0017] The 5-aryl-4 (R) -arylcarbonylamino-pent-2enoic acid amide substance P antagonist is poorly soluble in water as defined herein. It has a water solubility below 0.001%, for example 0.001 to 0.0001%.

[0018] The active agent is preferably used as a free base.

[0019] In a third aspect the present invention provides a microemulsion preconcentrate comprising a 5-aryl-4 (R) arylcarbonylamino-pent-2-enoic acid amide substance antagonist and a carrier medium comprising a lipophilic component and a surfactant.

[0020] In a fourth aspect the present invention provides a microemulsion preconcentrate comprising a 5-aryl-4 (R) arylcarbonylamino-pent-2-enoic acid amide substance antagonist and a carrier medium comprising a lipophilic component , a surfactant, and additionally a hydrophilic component.

[0021] The microemulsion preconcentrate preferably forms a microemulsion o / w (oil in water) when diluted with water.

[0022] Preferably the relative proportions of the lipophilic component, the hydrophilic component, and the surfactants are in the "Microemulsion" region in a standard three-way graph. These phase diagrams can be generated in a conventional manner as described for example in GB 2,222,770 or WO 96/13273.

[0023] In a fifth aspect the present invention provides a microemulsion comprising 5-aryl-4 (R) -arylcarbonylaminopent-2-enoic acid amide substance antagonists and a carrier medium comprising a lipophilic component and a surfactant.

[0024] The microemulsion is preferably a microemulsion o / w (oil in water).

[0025] In a sixth aspect the present invention provides a microemulsion comprising a 5-aryl-4 (R) -arylcarbonylaminopent-2enoic acid amide substance antagonist, a lipophilic component, a surfactant, water, and additionally a component hydrophilic

[0026] The colloidal structures of the microemulsion form spontaneously or substantially spontaneously when the components of the composition of the invention are brought into contact with an aqueous medium, for example by simple manual agitation for a short period, for example for 10 seconds. The compositions of the invention are thermodynamically stable, for example for at least 15 minutes or up to 4 hours, even up to 24 hours. Typically, they contain dispersed structures, ie liquid droplets or nanoparticles of an average diameter of less than about 200 nm (2,000 A), for example less than about 150 nm (1,500 A), typically less than 100 nm (1,000 Å), generally more than 10 nm (100 A) when measured by standard light scattering techniques, for example using a MALVERN ZETASIZER 3000 ™ particle characterization machine.

[0027] Solid drug particles of medium diameter of more than 200 nm may also be present. The proportion of particles present may be temperature dependent.

[0028] The active agent is a neuroquinine antagonist (NK antagonist) and is therefore capable of preventing disease symptoms that originate inter alia by activating the NK1 receptor by substance P and activating the NK2 receptor by neuroquinine A [= NKA] The antagonistic effects of substance P can be demonstrated, for example, as follows: in vitro, for example, the binding of substance P 3H to the bovine retina in the radioreceptor assay according to H. Bittiger, Ciba Foundation Symposium 91 ( 1982) 196-199, it is inhibited with IC50 values of approximately 0.2 nM.

[0029] More specifically the active agent is a 5-aryl-4 (R) -arylcarbonylamino-pent-2-enoic acid amide substance antagonist. This class of compounds is described in WO 98/07694.

[0030] Preferred active agents, which are described in WO 98/07694, include:

(4R) - [N'-methyl-N '- (3,5-bistrifluoromethylbenzoyl) -amino] -5- (1-methyl-indole-) N - [(R) -epsyloncaprolactam-3-yl] -amide 3-il) -pent-2-enoico,

(4R) - [N'-methyl-N '- (3,5-bistrifluoromethylbenzoyl) -amino] -5- (1-methyl-indole-) N - [(S) -epsyloncaprolactam-3-yl] -amide 3-il) -pent-2-enoico,

N-cyclohexylamide (4R) - [N’-methyl-N ’- (3,5-bistrifluoromethyl-benzoyl) -amino] -5- (1-methyl-indole-3-yl) -pent-2-enoic acid,

(4R) - [N'-methyl-N '- (3,5-bistrifluoromethyl-benzoyl) -amino] -5- (1-methyl-indole-3-yl) -2-methyl-pent acid N-cyclohexyl amide -2-enoic,

(4R) - [N'-methyl-N '- (3,5-bistrifluoromethylbenzoyl) -amino] -5- (1-methyl-) N - [(R) -epsilon-caprolactam-3-yl] -amide indole-3-yl) -2-methyl-pent-2-enoic,

(4R) - [N'-methyl-N '- (3,5-bistrifluoromethylbenzoyl) -amino] -5- (1-methyl-) N - [(S) -epsilon-caprolactam-3-yl] -amide indole-3-yl) -2-methyl-pent-2-enoic,

(4R) - (N'-methyl-N'-benzoyl-amino) -5- (1-methyl-indole-3-yl) -2 - N ([(R) -epsilon-caprolactam-3-yl] -amide -methyl-pent-2-enoic,

(4R) - [N'-methyl-N '- (3,5-bistrifluoromethylbenzoyl) -amino] -5- (naft-2-) N - [(R) -epsilon-caprolactam-3-yl] -amide il) -pent-2-enoico,

(4R) - (N'-methyl-N'-benzoyl) -amino-5- (naft2-yl) -pent-2-enoic acid N - [(R) -epsilon-caprolactam-3-yl] -amide ,

(4R) - [N'-methyl-N '- (3,5-bistrifluoromethylbenzoyl) -amino] -5- (naft-2-) N - [(R) -epsilon-caprolactam-3-yl] -amide il) -2-methyl-pent-2-enoic,

(4R) - [N'-methyl-N '- (3,4,5-trimethoxybenzoyl) -amino] -5- (naft-2-) N - [(R) -epsyloncaprolactam-3-yl] -amide il) -2-methyl-pent-2-enoic,

(4R) - [N'-methyl-N '- (3,5-bistrifluoromethylbenzoyl) -amino] -5- (naft-2-) N - [(S) -epsilon-caprolactam-3-yl] -amide il) -2-methyl-pent-2-enoic,

(4R) - [N'-methyl-N '- (3,5-bistrifluoromethyl-benzoyl) -amino] -5 (naphth-2-yl) -2-methyl-pent-2- acid N-cyclohexyl amide angry

(4R) - [N'-methyl-N '- (3,5-bistrifluoromethylbenzoyl) -amino] -5- (1-methyl-indole-) N - [(S) -epsyloncaprolactam-3-yl] -amide 3-il) -pent-2-enoico,

(4R) - [N'-methyl-N '- (3,5-bistrifluoromethylbenzoyl) -amino] -4- (4-chlorobenzyl) -but N-[(R) -epsyloncaprolactam-3-yl] -amide -2-enoic,

(4R) - [N'-methyl-N '- (3,5-bistrifluoromethylbenzoyl) -amino] -4- (4-chlorobenzyl) -but N-[(S) -epsyloncaprolactam-3-yl] -amide -2-enoic,

N-cyclohexylamide (4R) - [N’-methyl-N ’- (3,5-bistrifluoromethyl-benzoyl) -amino] -4- (4-chlorobenzyl) -but-2-enoic acid,

N-cyclohexylamide (4R) - [N’-methyl-N ’- (3,5-bistrifluoromethyl-benzoyl) -amino] -4- (3,4-dichlorobenzyl) -but-2-enoic acid,

5 (4R) - [N'-methyl-N '- (3,5-bistrifluoromethyl-benzoyl) -amino] -4- (3,4-difluorobenzyl) -but-2-enoic acid, N-cyclohexylamide N-cyclohexylamide (4R) - [N'-methyl-N '- (3,5-bistrifluoromethyl-benzoyl) -amino] -5- (4-chlorophenyl) -2-methyl-pent-2-enoic acid, N - [(R) - epsilon-caprolactam-3-yl] -amide (4R) - [N'-methyl-N '- (3,5-bistrifluoromethylbenzoyl) -amino] -5- (4-chlorophenyl) -2-methyl-pent- 2-enoic, [(S) -epsilon-caprolactam-3-yl] -amide (4R) - [N'-methyl-N '- (3,5-bistrifluoromethylbenzoyl) -amino] -4- (4- Chlorobenzyl) -2-methyl-but-2-ene, N - [(S) -epsyloncaprolactam-3-yl] -amide (4R) - [N'-ethyl-N '- (3,5-bistrifluoromethylbenzoyl) -amino] -5- (4-chlorophenyl) -pent-2-enoic acid (4R) N-cyclohexyl amide - [N'-methyl-N '- (3,5-bistrifluoromethyl-benzoyl) -amino] -5- (4-Chlorophenyl) -3-methyl-pent-2-enoic, [(R) -epsilon-caprolactam-3-yl] -amide (4R) - [N'-methyl-N '- (3, 5-bistrifluoromethylbenzoyl) -amino] -4- (4-chlorobenzyl) -3-methyl-but-2-enoic, N - [(R) -epsyloncaprolactam-3-yl] -amide of (4R) - [N'-methyl-N '- (3,5-bistrifluoromethylbenzoyl) -amino] -4- (4-chlorobenzyl) -but-2-enoic acid, N - [(R) -epsilon (4R) -4- [N'-methyl-N '- (3,5-bistrifluoromethyl-benzoyl) -amino] -4- (3,4-dichlorobenzyl) -but-2 -caprolactam-3-yl] -amide -enoic acid, N - [(R) -epsilon-caprolactam-3-yl] -amide (4R) -y (4S) -4- [N'-methyl-N '- (3,5bistrifluoromethyl-benzoyl) - amino] -4- (3-fluoro-4-chlorobenzyl) -but-2-enoic, N - [(R) -epsilon-caprolactam-3-yl] -amide (4R) -y (4S) -4 - [N'-methyl-N '- (3,5bistrifluoromethyl-benzoyl) -amino] -4- (3,4-difluorobenzyl) -but-2-enoic, N - [(R) -epsilon-caprolactam-3- (4R) -y (4S) -4- [N'-methyl-N '- (3,5-bistrifluoromethyl-benzoyl) -amino] -4- (3,4-dibromobenzyl) -but-2 -enoic acid, N - [(R) -epsilon-caprolactam-3-yl] -amide (4R) -y (4S) -4- [N'-methyl-N '- (3,5bistrifluoromethyl-benzoyl) - amino] -4- (3,4,5-trifluorobenzyl) -but-2-enoic acid, N - [(R) -epsilon-caprolactam-3-yl] -amide (4R) -y (4S) -4 - [N'-methyl-N '- (3,5bistrifluoromethyl-benzoyl) -a mino] -4- (4-fluorobenzyl) -but-2-enoic, N - [(S) -epsilon-caprolactam-3-yl] -amide (4R) -y (4S) - [N '- ( 3,5-Bistrifluoromethylbenzoyl) -N'-methyl-amino] -5,5-diphenyl-pent-2-enoic, N - [(R) -epsilon-caprolactam-3-yl] -amide acid (4S) - 4- [N'-methyl-N '- (3,5-bistrifluoromethylbenzoyl) amino] -4- (3,4-dichlorobenzyl) -but-2-enoic, N - [(S) -epsilon-caprolactam-3-yl] -amide of (4R) -4- [N'-methyl-N '- (3, Sbistrifluoromethylbenzoyl) amino] -4- (3,4-dichlorobenzyl) -but-2-enoic acid, and N - [(S) -epsilon-caprolactam-3-yl] -amide (4S) -4- [N'-methyl-N '- (3,5bistrifluoromethylbenzoyl) amino] -4- (3,4-dichlorobenzyl) -but-2- angry. [0031] The especially preferred active agent is (4R) -4- [N'-methyl-N '- (3,5-bistrifluoro-) N - [(R) -epsilon-caprolactam-3-yl] -amide methylbenzoyl) amino] -4- (3,4-dichlorobenzyl) -but-2enoic acid, that is, a compound of Formula I

image 1

[0032] This compound as referred to herein as Compound A.

[0033] Preferred and especially preferred active agents, in the form of a pharmaceutically acceptable or free salt, can be prepared as described in international patent application WO 98/07694. As mentioned herein, they may be in the form of their hydrates and / or may include other solvents, for example solvents that have been used for crystallization of compounds in solid form.

[0034] In accordance with the present invention the active agent may be present in an amount by weight of up to about 20% by weight of the composition of the invention, for example about 0.05% by weight. The active agent is preferably present in an amount of 0.5 to 15% by weight of the composition, more preferably in an amount of 1.5 to 5% by weight of the composition.

[0035] The active agent is poorly soluble in water since this is carried out in a carrier medium.

[0036] In the compositions of the invention the carrier medium comprises a lipophilic component and a surfactant. In some embodiments, the carrier medium comprises a lipophilic component, a surfactant and additionally a hydrophilic component.

[0037] The lipophilic component comprises one or more lipophilic substances. The hydrophilic component comprises one or more hydrophilic substances, and the carrier medium may contain one or more surfactants.

[0038] The compositions of the invention may include a variety of additives that include antioxidants, antimicrobial agents, enzyme inhibitors, stabilizers, preservatives, flavorings, sweeteners and additional components such as those described in Fiedler, HP "Lexikon der Hilfsstoffe für Pharmazic, Kosmetik und angrenzende Gebiete ", Editio Cantor, D-7960 Aulendorf, 4th revised and expanded edition (1996). These additives will conveniently dissolve in the carrier medium.

[0039] The compositions of the invention include a lipophilic component or phase. The active agent may be contained in this component of the carrier medium.

[0040] The lipophilic component is preferably characterized by a low HLB value of less than 10, for example up to 8. Suitable lipophilic components include:

1) C6-C14 mono-glyceryl fatty acid esters.

[0041] These are obtained by esterifying glycerol with vegetable oil followed by molecular distillation. Suitable monoglycerides for use in the compositions of the invention include symmetric monoglycerides (ie β-monoglycerides) as well as asymmetric monoglycerides (αmonoglycerides). They also include uniform glycerides (in which the fatty acid constituent is mainly composed of a single fatty acid) as well as mixed glycerides (i.e. in which the fatty acid constituent is composed of several fatty acids). Fatty acid may include saturated and unsaturated fatty acids having a chain length of for example C8-C14. Particularly suitable monoglycerides are lauric and caprylic acid monoglycerides which are commercially available, for example under the trade names Imwitor® 308 or Imwitor® 312, respectively, of for example sasol. For example, Imwitor® 308 comprises at least 80% monoglycerides and exhibits the following additional characteristic data: free glycerol max 6%, max. Acid value 3, saponification value 245-265, max. Iodine value 1, max. Water content 1%. Typically this comprises 1% free glycerol, 90% monoglycerides, 7% diglycerides, 1% triglycerides (H. Fiedler, loc. Cit., Volume 1, page 798). An additional example is Capmul MCM C8 from Abitec Corporation.

2) Mixtures of mono-and di-glycerides of C6-C18 fatty acids

[0042] These include symmetric mono- and di-glycerides (ie β-monoglycerides and α, α1diglycerides) as well as asymmetric mono- and di-glycerides (ie α-monoglycerides and α, βdiglycerides) and their acetylated derivatives. They also include uniform glycerides (in which the fatty acid constituent is mainly composed of a single fatty acid) as well as mixed glycerides (i.e. in which the fatty acid constituent is composed of several fatty acids) and any derivatives of the same with citric or lactic acid. The fatty acid constituent may include saturated and unsaturated fatty acids having a chain length of for example C8-C10. Particularly suitable mono- and di-glycerides are mixed with commercially available capric and caprylic acid, for example under the trade name Imwitor® 742 or Imwitor 928, for example sasol. For example, Imwitor® 742 which comprises at least 45% monoglycerides and exhibits the following additional characterization data: max. 2% free glycerol, max. acid value 2, saponification value 250-280, max. iodine value 1, max. 2% water (H. Fiedler, loc. cit., vol 1, page 798). Other suitable mixtures comprise mono / diglycerides of caprylic / capric acid in glycerol as is known and commercially available under for example the trade name Capmul® MCM from for example Abitec Corporation. Capmul® MCM exhibits the following additional characterization data: max. Acid value 2.5, alpha-Mono (as oleate) 80% min., Free glycerol 2.5% max., Iodine value 1 max., Chain length distribution: caproic acid (C6) 3% max., Caprylic acid (C8 ) 75% min., Capric acid (C10) 10% min., Lauric acid (C12) 1.5% max., Humidity (by Karl Fisher) 0.5% max. (manufacturer information). Suitable examples of mono- / diglycerides with additional derivation with lactic or citric acid are those marketed under the brand names Imwitor 375, 377 or 380 by sasol. Additionally, the fatty acid constituent may include saturated and unsaturated degrees acids having a chain length of for example C16-C18. A suitable example is Tegin® O (glyceryl oleate) exhibits the following additional characterization data: monoglyceride content 55-65%, max. peroxide value 10, max. water content 1%, max. acid value 2, iodine value 70-76, saponification value 158-175, max. 2% free glycerol, (manufacturer information).

3) C6-C18 di-glyceryl fatty acid esters

[0043] These include symmetric diglycerides (ie α, α1-diglycerides) and asymmetric (ie α, β-diglycerides) and their acetylated derivatives. They also include uniform glycerides (in which the fatty acid constituent is mainly composed of a single fatty acid) as well as mixed glycerides (i.e. in which the fatty acid constituent is composed of several fatty acids) and any acetylated derivatives thereof. The fatty acid constituent may include saturated and unsaturated fatty acids having a chain length of C6-C18, for example C6-C16, for example C8-C10, for example C8. Particularly suitable capril diglycerides, which are commercially available, for example under the trade name Sunfat® GDC-S, for example from Taiyo Kagaku Co., Ltd. Sunfat® GDC-S has an acid value of about 0.3, a diglyceride content of about 78.8%, and a monoester content of about 8.9.

4) Medium chain fatty acid triglyceride

[0044] These include triglycerides of saturated fatty acids having 6 to 12, for example 8 to 10, carbon atoms. Suitable medium chain fatty acid triglycerides are those known and commercially available under the trade names Acomed®, Myritol®, Captex®, Neobee®M 5 F, Miglyol®810, Miglyol®812, Miglyol®818, Mazol®, Sefsol ®860, Sefsol®870; Miglyol®812 being the most preferred. Miglyol®812 is a fractionated coconut oil comprising triglycerides of caprylic acid-capric acid and having a molecular weight of approximately 520 Daltons. Fatty acid composition = C6 max. about 3%, C8 about 50 to 65%, C10 about 30 to 45%, C12 max 5%; acid value about 0.1; saponification value approximately 330 to 345; iodine value max 1. Miglyol® 812 is available from Condea. Neobee® M 5 F is a triglyceride of caprylic acid-fractionated capric acid available from coconut oil; max. acid value 0.2; saponification value approximately 335 to 360; iodine value max 0.5, max. water content 0.15%, D.20 0.9300.960, nD 20 1,448-1,451 (manufacturer information). The Neobee® M 5 F is available from Stepan Europe. An additional example is Miglyol 829 which additionally contains esters with succinic acid.

5) C16-C18 mono-glyceryl fatty acid esters

[0045] These are obtained by esterifying glycerol with vegetable oil followed by molecular distillation. Suitable monoglycerides for use in the compositions of the invention include symmetric monoglycerides (ie β-monoglycerides) as well as asymmetric monoglycerides (αmonoglycerides). They also include uniform glycerides (in which the fatty acid constituent is mainly composed of a single fatty acid) as well as mixed glycerides (i.e. in which the fatty acid constituent is composed of several fatty acids). The fatty acid constituent may include saturated and unsaturated fatty acids having a chain length of for example C16-C18. Suitable examples include GMOrphic by Estman, Rylo MG20 monoglyceride distilled by Danisco ingredients, or Monomuls 90-018 by Henkel. For example, GMOrphic®-80 (glyceryl monooleate) exhibits the following additional characterization data: monoglyceride content min. 94%, C18: 1 content 75% min., Max. peroxide value 2.5, C18: 2 + C18: 3 max. 15%, C16: 0 + C18: 0 + C20: 0 max. 10%, max. water 2%, max. acid value 3, iodine value 65-75, saponification value 155-165, max. Free glycerin 1%, hydroxyl number 300-330 (manufacturer information).

6) Mono-, di-, tri-glycerides mixed

[0046] These include mixed mono-, di-, tri-glycerides that are commercially available under the trade name Maisine® from Gattefossé. They are transesterification products of corn oil and glycerol. Such products predominantly comprise mono-, di- and tri-glycerides of linoleic and oleic acid together with minor amounts of mono-, di- and tri-glycerides of stearic or palmitic acid (corn oil itself is comprised of ca. 56% by weight of linoleic acid, 30% of oleic acid, ca. 10% of constituents of palmitic acid and ca. 3% of stearic acid). The physical characteristics are: free glycerol max 10%, monoglycerides ca. 40%, diglycerides ca. 40%, triglycerides ca. 10%, the content of free oleic acid ca. one%. The additional physical characteristics are: max. acid value 2, iodine value of 85-105, saponification value of 150-175, mineral acid content = 0. The fatty acid content for Maisine® is typically: palmitic acid ca. 11%, stearic acid ca. 2.5%, oleic acid ca. 29%, linoleic acid ca. 56%, others ca. 1.5% (H. Fiedler, loc. Cit., Volume 2, page 958; manufacturer information).

[0047] The mixed mono-, di-, tri-glycerides preferably comprise mixtures of mono-, di- and tri-glycerides of C8 to C10 or C12-20 fatty acids, especially mono-, di- and triglycerides of mixed fatty acid. C16-18. The fatty acid component of the mixed mono-, di- and triglycerides may comprise saturated and unsaturated fatty acid residues. Preferably, however, they are predominantly comprised of unsaturated fatty acid residues; in particular C18 unsaturated fatty acid residues. Suitable mixed mono-, di-, tri-glycerides comprise at least 60%, preferably at least 75%, more preferably at least 85% by weight of C18 unsaturated fatty acid mono-, di-and tri-glycerides (for example linolenic, linoleic and oleic acid). Suitable mixed mono-, di-, tri-glycerides comprise less than 20%, for example about 15% or 10% by weight or less, mono-, di- and tri-glycerides of saturated fatty acid (for example palmitic acid and stearic). The mixed mono-, di-, tri-glycerides preferably comprise predominantly mono- and diglycerides; for example, mono- and di-glycerides comprise at least 50%, more preferably at least 70% based on the total weight of the lipophilic phase or the component. More preferably, the mono- and di-glycerides comprise at least 75% (for example about 80% or 85% by weight of the lipophilic component. Preferably the monoglycerides comprise about 25 to about 50%, based on the total weight of the component lipophilic, of the mixed mono-, di-, triglycerides More preferably from about 30 to about 4-0% (for example 35 to 40%) monoglycerides are present, preferably the diglycerides comprise from about 30 to about 60%, based in the total weight of the lipophilic component, of the mixed mono-, di-, tri-glycerides More preferably from about 40 to about 55% (for example 48 to 50%) diglycerides are present, suitable triglycerides comprise at least 5 % but less than about 25%, based on the total weight of the lipophilic component, of the mixed mono-, di-, tri-glycerides More preferably they are present in apr about 7.5 to about 15% (for example about 9 to 12%) of triglycerides. The mixed mono-, di-, tri-glycerides can be prepared by mixing individual mono-, di- or tri-glycerides in appropriate relative proportion. They nevertheless conveniently comprise transesterification products of vegetable oils, for example almond oil, ground nut oil, olive oil, peach oil, palm oil or, preferably, corn oil, sunflower oil or sesame oil and more preferably corn oil, with glycerol. Such transesterification products are generally obtained as described in GB 2 257 359 or WO 94/09211. Preferably some of the glycerol is first removed to give a "batch substantially free of glycerol" when soft gelatin capsules are made. Purified transesterification products of corn oil and glycerol particularly provide suitable mixed mono-, di-, and tri-glycerides referred to herein as "refined oil" and produced in accordance with the procedures described in the Kingdom patent specification United GB 2,257,359 or international patent publication WO 94/09211.

7) Acetylated Monoglycerides (C18)

[0048] These include Myvacet 9-45.

8) Propylene glycol fatty acid monoesters

[0049] The fatty acid constituent may include saturated and unsaturated fatty acids having a chain length of for example C8-C12. Particularly suitable are monoester propylene glycol of caprylic acid and lauric acid when commercially available, for example under the trade names Sefsol® 218, Capryol®90 or Lauroglycol®90, for example Nikko Chemicals Co., Ltd. or Gattefossé or Capmul PG- 8 from Abitec Corporation. For example, Lauroglycol®90 exhibits the following additional characteristic data: max. acid value 8, saponification value 200-220, max. iodine value 5, free propylene glycol content max. 5%, min. 90% monoester content; Sefsol® 218 exhibits the following additional characterization data: max. acid value 5, hydroxy value 220-280 (H. Fiedler, loc, cit., Vol 2, page 906, manufacturer information). 9) Mono- and di-esters of Propylene Glycol fatty acid [0050] These include Laroglycol FCC and Capryol PGMC. 10) Propylene glycol diesters [0051] Propylene glycol fatty acid diesters such as propylene glycol dicaprylate (which is commercially available under the trade name Miglyol® 840 for example sasol; H. Fiedler, loc. Cit., Volume 2, page 1008 ) or Captex 200 of Abitec Corporation. 11) Propylene glycol monoacetate and propylene glycol diacetate 12) Transesterified ethoxylated vegetable oils [0052] These include transesterified ethoxylated vegetable oils such as those obtained by reacting various natural vegetable oils (eg, corn oil, grain oil, almond oil , ground nut oil, olive oil, soybean oil, sunflower oil, sesame oil and palm oil, or mixtures thereof) with polyethylene glycols having an average molecular weight of 200 to 800, in the presence of an appropriate catalyst . These procedures are described in the US patent specification US 3,288,824. Transesterified ethoxylated corn oil is particularly preferred. [0053] Transesterified ethoxylated vegetable oils are known and are commercially available under the trade name Labrafil® (H. Fiedler, loc. Cit., Vol 2, page 880). Examples are Labrafil® M 2125 CS (obtained from corn oil and have an acid value of less than about 2, a saponification value of 155 to 175, an HLB value of 3 to 4, and an iodine value of 90 to 110), and Labrafil® M 1944 CS (obtained from grain oil and having an acid value of approximately 2, a saponification value of 145 to 175 and an iodine value of 60 to 90). Labrafil® M 2130 CS (which is a transesterification product of a C12-18 glyceride and polyethylene glycol and having a melting point of approximately 35 to 40 ° C, an acid value of less than about 2, can also be used a saponification value of 185 to 200 and an iodine value of less than about 3). The preferred transesterified ethoxylated vegetable oil is Labrafil® M 2125 CS which can be obtained, for example, from Gattefossé, Saint-Priest Cedex, France. 13) Sorbitan fatty acid esters [0054] Such esters include, for example, C12-18 fatty acid monoesters of sorbitan, or C12-18 fatty acid triesters of sorbitan are commercially available under the trademark Span® of for example uniqema. An especially preferred product of this class is for example Span® 20 (sorbitan monolaurate) or Span® 80 (sorbitan monooleate) (Fiedler, loc. Cit., 2, p. 1430; Handbook of Pharmaceutical Excipients, loc. Cit. , page 473). 14) Esterified fatty acid compounds and primary alcohols

11 [0055] These include esterified fatty acid compounds having 8 to 20 carbon atoms and primary alcohol having 2 to 3 carbon atoms, for example, isopropyl myristate, isopropyl palmitate, ethyl linoleate, ethyl oleate, ethyl myristate etc. ., with an esterified compound of linoleic acid and ethanol, also isopropylmiristate and isopropylpalmitate, is particularly preferable. 15) Glycerol triacete or (1,2,3) -triacetin [0056] This is obtained by esterifying glycerin with acetic anhydride. Glycerol triacetate is commercially available as, for example Priacetin® 1580 from Unichema International, or as Eastman ™ Triacetin from Eastman, or from Courtaulds Chemicals Ltd. Glycerol triacetate exhibits the following additional characterization data: molecular weight 218.03, D.20.3 1,159-1,163, nD 20 1,430-1,434, max. water content 0.2%, viscosity (25 °) 17.4 mPa s, max. acid value 0.1, saponification value of approximately 766-774, triacetin content 97% min. (H. Fiedler, loc. Cit., Vol 2, page 1580; Handbook of Pharmaceutical Excipients, loc. Cit., Page 534, manufacturer information). 16) Acetyl triethyl citrate [0057] Obtained by esterification of citric acid and ethanol, followed by acetylation with acetic anhydride, respectively. Acetyl triethyl citrate is commercially available, for example under the trade name Citroflex® A-2, for example Morflex Inc. 17) Tributyl citrate or acetyl tributyl citrate 18) Polyglycerol fatty acid esters [0058] These have as example from 2 to 10, for example 6 units of glycerol. The fatty acid constituent may include saturated and unsaturated fatty acids having a chain length of for example C8-C18. Particularly suitable is for example Plurol Oleique CC497 from Gattefossé, which has a saponification value of 133-155 and a saponification value of 196-244. Additional suitable polyglycerol fatty esters include diglyceryl monooleate (DGMO) and Hexaglin-5-O, as is known and commercially available from eg Nikko Chemicals Co., Ltd. 19) PEG fatty alcohol ether [0059] This includes lauryl ether Brij 30 ™ polyoxyethylene (4). 20) Fatty alcohols and fatty acids [0060] Fatty acids can be obtained by hydrolyzing various vegetable fats or oils, such as olive oil, followed by separation of liquid acids. The fatty acid / alcohol constituent may include mono- or di-fatty acids / saturated or unsaturated alcohols having a chain length of for example C6-C20. Particularly suitable are, for example, oleic acid, oleyl alcohol, linoleic acid, capric acid, caprylic acid, caproic acid, tetradecanol, dodecanol, or decanol. Oleyl alcohol is commercially available under the trademark HD-Eutanol® V for example Henkel KGaA. Oleyl alcohol exhibits the following additional characterization data: max. acid value 0.1, hydroxy value of about 210, iodine value of about 95, saponification value max 1, D.20 about 0.849, nD 20 1.462, molecular weight 268, viscosity (20 °) about 35 mPa s (manufacturer information ). Oleic acid exhibits the following additional characterization data: molecular weight 282.47,

D.20 0.895, nD 20 1.45823, acid value 195-202, iodine value 85-95, viscosity (25 °) 26 mPa s

(H. Fiedler, loc. Cit., Volume 2, page 1112; "Handbook of Pharmaceutical Excipients", 2nd Edition, Editors A. Wade and PJ Weller (1994), Joint publication of American Pharmaceutical Assoc., Washington, USA and The Pharmaceutical Press, London, England, page 25).

21) Tocopherol and its derivatives (for example acetate)

12 [0061] These include Coviox T-70, Copherol 1250, Copherol F-1300, Covitol 1360 and Covitol 1100. 22) Pharmaceutically acceptable oils [0062] Alternatively, the lipophilic component comprises, for example, a pharmaceutically acceptable oil, preferably with an unsaturated component. such as a vegetable oil. 23) Polyol alkylene esters or ethers [0063] These include C3-5 alkylene triols, in particular glycerol, ethers or esters. Ethers

or suitable tri-C3-5 alkylene esters include mixed ethers or esters, ie components that include other ether or ester ingredients, for example transesterification products of C3-5 triol alkylene esters with other mono-, di- or polyols. Particularly suitable alkylene ethers and esters, C3-5 triol alkylene / poly- (C2-4 alkylene) fatty acid esters, especially glycerol / polyethylene- or polypropylene glycol fatty acid esters are mixed. Especially suitable polyol alkylene ethers or esters include products obtainable by transesterification of glycerides, for example triglycerides, with poly (C2-4 alkylene) glycols, for example poly-ethylene glycols and, optionally, glycerol. Such transesterification products are generally obtained by glyceride alcohololysis, for example triglycerides, in the presence of a poly- (C-2-4 alkylene) glycol, for example polyethylene glycol and, optionally, glycerol (ie to effect glyceride transesterification for the poly-alkylene glycol / glycerol component, ie by means of poly-alkylene glycol / glycerolysis). In general, such a reaction is carried out by reacting the indicated components (glyceride, polyalkylene glycol and, optionally, glycerol) at elevated temperature under an inert atmosphere with continuous stirring.

[0064] Preferred glycerides are triglycerides of fatty acids, for example triglycerides (C10-22 fatty acid), which include hydrogenated and natural oils, in particular vegetable oils. Suitable vegetable oils include, for example, olive, almond, peanut, coconut, palm, soybean and wheat germ oils and, in particular, natural or hydrogenated oils in ester residues of (C12-18 fatty acid). Preferred polyalkylene glycol materials are polyethylene glycols, in particular polyethylene glycols having a molecular weight of ca. 500 to ca. 4,000, for example of ca. 1,000 to ca. 2,000

[0065] Suitable polyol alkylene esters or esters include mixtures of tri-C3-5 alkylene esters, for example mono-, di- and tri-esters in varying relative amounts, and poly (C2-4 alkylene) glycol mono- and di-esters, together with minor amounts of free C3-5 tril alkylene and free poly- (C2-5 alkylene). As stated hereinbefore, the preferred triol alkylene functional group is glyceryl; Preferred polyalkylene glycol functional groups include polyethylene glycol, in particular with a molecular weight of ca. 500 to ca. 4,000; and the preferred fatty acid functional groups will be C10-22 fatty acid ester residues, in particular saturated C10-21 fatty acid ester residues.

[0066] Particularly suitable polyol alkylene ethers and esters include transesterification products of a natural or hydrogenated vegetable oil and a polyethylene glycol and, optionally, glycerol; or compositions comprising or consisting of mono-, di- and tri-esters of C10-22 glyceryl fatty acid and C10-22 mono- and di-esters of polyethylene glycol (optionally together, for example, minor amounts of free glycerol and free polyethylene glycol ).

[0067] Preferred vegetable oils, polyethylene glycol or polyethylene glycol functional groups and fatty acid functional groups in relation to the above definitions are as set forth below.

[0068] Preferred suitable polyol alkylene ethers and esters as described above for use in the present invention include those commercially available under the trade name Gelucire® of for example Gattefossé, in particular the products:

a) Gelucire® 33/01, which have a m.p. = ca. 33-37 ° C and a saponification value of

AC. 230-255;

b) Gelucire® 39/01, m.p. = ca. 37.5-41.5 ° C, saponification v. = ca. 225-245;

c) Gelucire® 43/01, m.p. = ca. 42-46 ° C, saponification v. = ca. 220-240;

[0069] The above products (a) to (c) have a maximum acid value of 3. The compositions of the invention may include mixtures of such ethers or esters.

24) Hydrocarbons

[0070] These include, for example, squalene, available from, for example, Nikko Chemicals Co., Ltd.

25) Ethylene Glycol Esters

[0071] These include Monthyle® (ethylene glycol monostearate), available from for example Gattefossé.

26) Pentaerythriol fatty acid esters and polyalkylene glycol ethers

[0072] These include, for example pentaerythritol diolcate, -dystearate, -monolaurate, polyglycol ether, and -monostearate as well as pentaerythritol fatty acid esters (Fiedler, loc. Cit., 2, p. 1158-1160).

[0073] Some of these, for example (1-3, 5-6, 8-9, 12-13, 19), exhibit similar surfactant behavior and can also be referred to as co-surfactants.

[0074] The lipophilic component preferably comprises 5 to 85% by weight, of the composition of the invention, for example 10 to 85%; preferably 15 to 60% by weight, more preferably about 20 to about 40% by weight.

[0075] For these embodiments wherein the carrier medium comprises a hydrophilic component in addition to the lipophilic component and the relative proportions of the lipophilic component surfactant, hydrophilic component and the surfactant is within the "Microemulsion" region in a graph of three standard tracks

[0076] The compositions of the invention may include a hydrophilic phase or component.

[0077] Suitable hydrophilic compounds include:

1) C6-C10 polyethylene glycol glyceryl fatty acid esters

[0078] The fatty acid ester may include mono and / or di and / or tri esters of fatty acids. This optionally includes saturated and unsaturated fatty acids having a chain length of for example C8-C10. The polyethylene glycols can have for example 5 to 10 units [CH2-CH2-O], for example 7 units. A particularly suitable fatty acid ester is polyethylene glycol glyceryl monococoate (7), which is commercially available, for example under the trade name Cetiol® HE, for example from Henkel KGaA. Cetiol® HE has a D. (20 °) of 1.05, an acid value of less than 5, a saponification value of approximately 95, a hydroxyl value of approximately 180 and an iodine value of less than 5 ( H. Fiedler, loc. Cit., Vol 1, page 337) or Lipestrol E-810.

2) N-alkyl pyrrolidone

[0079] It is particularly suitable, for example N-Methyl-2-pyrrolidone, for example when it is available under the trade name Pharmasolve ™, for example International Specialty Products (ISP). N-methylpyrrolidone exhibits the following additional characterization data: weight 99.85% min (H. Fiedler, loc. Cit., Vol 2, page 1004, manufacturer information).

3) Benzyl alcohol

[0080] This is commercially available from, for example, Merck or can be obtained by distillation of benzyl chloride or potassium or sodium carbonate. Benzyl alcohol exhibits the following additional characterization data: molecular weight 108.14, D. 1.043-1.049, nD 1.5381.541. (H. Fiedler, loc. Cit., Vol 1, page 238; Handbook of Pharmaceutical Excipients, loc. Cit., Page 35).

4) Triethyl Citrate

[0081] It is obtained by esterifying citric acid and ethanol. Triethyl citrate is commercially available, for example under the trade names Citroflex® 2, or in a pharmaceutical grade under the name TEC-PG / N, for example Morflex Inc. Triethyl citrate having a molecular weight of 276 is particularly suitable , 3, a specific gravity of 1,135-1,139, a refractive index of 1,439-1,441, a viscosity (25 °) of 35.2 mPa s, test (anhydrous base) 99,0100.5%, max. water 0.25% (Fiedler, H. P., loc. cit. ,, vol 1, page 371; "Handbook of Pharmaceutical Excipients", loc. cit., page 540).

[0082] Other suitable hydrophilic compounds include transcutol (C2Hs- [O- (CH2) 2] 2-OH), glycolurol (also known as tetrahydrofurfuryl alcohol polyethylene glycol ether), 1,2-propylene glycol, dimethylisorbide (Arlasolve), polyethylene glycol, triethylene glycol, ethylacetate, and ethylactate.

[0083] The hydrophilic component may comprise 5 to 60% by weight of the composition of the invention, for example 10 to 50%; preferably 10 to 40% by weight, more preferably about 10 to about 30% by weight.

[0084] The hydrophilic component may comprise a mixture of two or more hydrophilic components.

[0085] The compositions of the invention may be lower alkanols such as ethanol as a hydrophilic co-component. Although the use of ethanol in the compositions is not essential, it has been found to be a particular advantage when the arc compositions are manufactured in the form of a soft gelatin capsule. This is because the storage characteristics are improved, in particular the risk of precipitation of the active agent is reduced after encapsulation procedures. Thus, the shelf life stability can be extended by using ethanol or some other cocomponent as an additional ingredient of the composition. The ethanol may comprise 0 to 60% by weight of the composition; preferably 5 to about 30% by weight and more preferably about 5 to 20% by weight.

[0086] The compositions of the present invention contain one or more surfactants to reduce interfacial tension to thereby provide thermodynamic stability.

[0087] Surfactants may be complex mixtures containing collateral products

or non-reaction starting products involved in its preparation, for example the surfactants made by polyoxyethylation may contain another collateral product, for example polyethylene glycol. The or each surfactant preferably has a hydrophilic-lipophilic (HLB) balance value of 8 to 17, especially 10 to 17. The HLB value is preferably the average HLB value.

[0088] Suitable surfactants include: 1) Reaction products of a hydrogenated or natural castor oil and ethylene oxide [0089] Hydrogenated or natural castor oil can be reacted with ethylene oxide

in a molar ratio of about 1:35 to about 1:60, with optional removal of the polyethylene glycol component from the products. Several such surfactants are commercially available. Particularly suitable surfactants include hydrogenated castor oils of polyethylene glycol available under the trade name Cremophor®; Cremophor® RH 40, which has a saponification value of about 50 to 60, an acid value of less than about 1, a water content (Fischer) of less than about 2%, an nD 60 of about 1,453-1,457 and an HLB of about 14-16; and Cremophor® RH 60, which has a saponification value of about 40-50, an acid value of less than about 1, an iodine value of less than about 1, a water content (Fischer) of about 4.5-5.5 %, an nD 60 of approximately 1,453-1,457 and an HLB of approximately 15 to 17.

[0090] An especially preferred product of this class is Cremophor® RH40. Other useful products of this class are available under the trade names Nikkol® (for example Nikkol®

[0091] HCO-40 and HCO-60), Mapeg® (for example Mapeg® CO-40h), Incrocas® (for example Incrocas® 40), Tagat® (for example polyoxyethylene-glycerol fatty acid esters for example Tagat ® RH 40) and Simulsol OL-50 (castor oil PEG-40, which has a saponification value of approximately 55 to 65, an acid value of max. 2, an iodine value of 25 to 35, a content of water of max 8%, and an HLB of approximately 13, available from Seppic). These surfactants are further described in Fiedler loc. cit.

[0092] Other suitable surfactants for this class include polyethylene glycol castor oils such as those available under the trade name Cremophor® EL, which have a molecular weight (by current osmometry) of approximately 1630, a saponification value of approximately 65 to 70, an acid value of about 2, an iodine value of about 28 to 32 and a nD 25 of about 1,471.

2) Polyoxyethylene sorbitan fatty acid esters

[0093] These include mono- and tri-esters of lauryl, palmityl, stearyl and oleyl of the known type and are commercially available under the trade name Tween® (Fiedler, loc. Cit. P.1615 ff) from Uniqema which include the products :

Tween® 20 [polyoxyethylene (20) sorbitan monolaurate],

Tween® 21 [polyoxyethylene (4) sorbitan rnorlolaurate],

Tween® 40 [polyoxyethylene (20) sorbitan monopalmitate],

Tween® 60 [polyoxyethylene (20) sorbitan monostearate],

Tween® 65 [polyoxyethylene (20) sorbitan tristearate],

Tween® 80 [polyoxyethylene (20) sorbiknmonooleate],

Tween® 81 [polyoxyethylene (5) sorbitan monooleate], and

Tween® 85 [polyoxyethylene (20) sorbitan trioleate].

[0094] Especially preferred products of this class are Tween® 20 and Tween® 80.

3) Polyoxyethylene fatty acid esters

[0095] These include polyoxyethylene stearic acid esters of the known type and commercially available under the trade name Myrj® from Uniqema (Fiedler, loc. Cit., 2, p. 1042). An especially preferred product of this class is Myrj® 52 which has a D25 of about 1.1., A melting point of about 40 to 44 ° C, an HLB value of about 16.9., An acid value of about 0 to 1 and A saponification no. from about 25 to 35.

4) Poloxamers or block copolymers and polyoxyethylene-polyoxypropylene copolymers

16 [0096] These include the type known and commercially available under the trade names Pluronic® and Emkalyx® (Fiedler, loc. Cit., 2, p. 1203). An especially preferred product of this class is BASF Pluronic® F68 (poloxamer 188), which has a melting point of about 52 ° C and a molecular weight of about 6800 to 8975. An additional preferred product of this class is Synpcronic® PE L44 (poloxamer 124) from Uniqema. 5) Polyoxyethylene monoesters of a saturated C10 to C22 [0097] These include C18 substituted for example hydroxy fatty acid; for example PEG ester of hydroxystearic acid 12, for example of PEG approximately for example 600-900 for example 660 Daltons MW, for example Solutol® HS 15 of BASF, Ludwigshafen, Germany. According to the technical brochure MEF 151E of BASF (1986) which comprises approximately 70% by weight 12 polyethoxylated hydroxystearate and approximately 30% by weight of non-esterified polyethylene glycol component. Solutol HS 15 has a hydrogenation value of 90 to 110, a saponification value of 53 to 63, an acid number of maximum 1, and a maximum water content of 0.5% by weight. 6) Polyoxyethylene alkyl ethers [0098] These include polyoxyethylene glycol ethers of C12 to C1x alcohols, for example Polyoxyl 2-, 10-or 20-octyl ether or Polyoxyl 23-lauryl ether, or polyoxyl 20-oleyl ether, or Polyoxyl 2-, 10-, 20-or 100-stearyl ether, as is known and commercially available for example under the trademark Brij® of Uniqema. An especially preferred product of this class is for example Brij® 35 (Polyoxyl 23 lauryl ether) or Brij® 98 (Polyoxyl 20 oleyl ether) (Fiedler, loc. Cit., 1, pp. 259; Handbook of Pharmaceutical Excipients, loc. cit., page 367). Similarly suitable products include polyoxyethylene-polyoxypropylene-alkyl ethers, for example polyoxyethylene-polyoxypropylene-ethers of C12 to C18 alcohols, for example polyoxyethylene-20-polyoxypropylene-4-cetyl ether which is known and commercially available under the trademark Nikkol PBC® 34, for example Nikko Chemicals Co., Ltd. (Fiedler, loc. Cit., Vol. 2, pp. 1239). Also suitable are polyoxypropylene fatty acid ethers, for example Acconon® E. 7) Alkyl sulfates and sodium sulphonates, and sodium alkyl aryl sulfonates [0099] These include sodium lauryl sulfate, which is also known as sodium dodecyl sulfate and are commercially available, for example under the trade name Texapon K12® from Henkel KGaA. 8) Water soluble polyethylene glycol tocopheryl succinic acid esters (TPGS) [0100] These include those with a polymerization number ca 1000, for example available from Eastman Fine Chemicals Kingsport, Texas, USA. 9) Polyglycerol fatty acid esters [0101] These include those with for example from 10 to 20, for example 10 glycerol units. The fatty acid constituent may include saturated and unsaturated fatty acids having a chain length of for example C8-C18. It is particularly suitable for example decaglycerylmonolaurate or decaglycerylmonomiristate, as it is known and commercially available under the trademark Decaglyn® 1-L or Decaglyn® 1-M or Decaglyn 1-O, respectively, for example Nikko Chemicals C., Ltd (Fiedler , loc. cit., vol. 2, pp. 1228). 10) Polyol alkylene esters or esters [0102] These include C3-5 alkylene triols, in particular glycerol, ethers or esters. Ethers

or suitable C3-5 alkylene esters include mixed ethers or esters, ie components that include other ester or ether ingredients, for example transesterification products of C3-5 triol alkylene esters with other mono-, di- or polyols. Particularly suitable alkylene ethers or esters are mixed with fatty acid esters triol C3-5 alkylene / poly (C2-4 alkylene) glycol, especially glycerol / polyethylene or polypropylene glycol fatty acid esters.

[0103] Especially suitable polyol alkylene ethers or esters include products obtainable by transesterification of glycerides, for example triglycerides, with poly (C24 alkylene) glycols, for example poly-ethylene glycols and, optionally, glycerol.

[0104] Such transesterification products are generally obtained by glyceride alcohololysis, for example triglycerides, in the presence of a poly (C-2-4 alkylene) glycol, for example polyethylene glycol and, optionally, glycerol (ie to effect transesterification of the glyceride with the poly-alkylene glycol / glycerol component, ie by means of polyalkylene glycolysis / glycerolysis). In general, such a reaction is carried out by reacting the indicated components (glyceride, polyalkylene glycol and, optionally, glycerol) at elevated temperature under an inert atmosphere with continuous stirring.

[0105] Preferred glycerides are triglycerides of fatty acids, for example triglycerides (C10-22 fatty acid), which include natural and hydrogenated oils, in particular vegetable oils. Suitable vegetable oils include, for example, olive, almond, peanut, coconut, palm, soy and wheat germ oils and, in particular, natural or hydrogenated oils rich in ester residues (C12-18 fatty acid).

[0106] Preferred polyalkylene glycol materials are polyethylene glycols, in particular polyethylene glycols having a molecular weight of ca. 500 to ca. 4,000, for example of ca. 1,000 to ca. 2,000

[0107] Suitable polyol alkylene esters or ethers include mixtures of tri-C3-5 alkylene esters, for example mono-, di- and tri-esters in varying relative amounts, and mono-di- and polyesters (C2-4 alkylene), together with amounts minor triol C3-5 alkylene and poly (C2-5 alkylene) free glycol. As stated hereinbefore, the preferred triol alkylene functional group is glyceryl; polyalkylene glycol functional groups include polyethylene glycol, in particular they have a molecular weight of ca. 500 to ca. 4,000; and the preferred fatty acid functional groups will be C10-22 fatty acid ester residues, in particular saturated C10-22 fatty acid ester residues.

[0108] Particularly suitable polyol alkylene ethers or esters include transesterification products of a natural or hydrogenated vegetable oil and a polyethylene glycol and, optionally, glycerol; or compositions comprising or consisting of C1022 mono-, di- and tri-esters of glyceryl fatty acids and C10-22 mono- and di-esters of polyethylene glycol (optionally together with, for example, minor amounts of free glycerol and free polyethylene glycol ).

[0109] Preferred vegetable oils, polyethylene glycol or polyethylene glycol functional groups and fatty acid functional groups in relation to the above definitions are as set forth above.

[0110] Particularly suitable ethers or polyol alkylene esters as described above for use in the present invention include those commercially available under the trade name Gelucire® of for example Gattefossé, in particular the products:

a) Gelucire® 44/14, m.p. = ca. 42.5-47.5 ° C, saponification v. = ca. 79-93;

b) Gelucire® 50/13, m.p. = ca. 46-51 ° C, saponification v. = ca. 67-81;

[0111] The products (a) to (b) above have an acid value of maximum of 2.

[0112] Generally polyol alkylene ethers or esters having an iodine value of maximum 2 are preferred. Compositions of the invention may include mixtures of ethers or esters.

[0113] Gelucire® products are inert semi-solid materials with amphiphilic character. They are identified by their melting point and their HLB value. The highest Gelucire® grades are saturated polyglycolized glycerides by polyglycolysis of natural hydrogenated vegetable oils with polyethylene glycols. They are composed of a mixture of mono-, di- and tri-glycerides and mono- and di-esters of polyethylene glycol fatty acid. Gelucire® 44/14 having a nominal melting point of 44 ° C and an HLB of 14. is particularly suitable. This is obtained by reacting hydrogenated palm kernels and / or hydrogenated palm oils with polyethylene glycol 1500. This consists of approximately 20% mono-, di- and triglycerides, 72% mono- and di-esters of 1500 polyethylene glycol fatty acid and 8% 1500 free polyethylene glycol. The distribution of fatty acid for Gelucire® 44/14 is as follows: 4- 10 C8, 3-9 C10, 40-50 C12, 14-24 C14, 4-14 C16, 5-15 C18. Gelucire® 44/14 exhibits the following additional characterization data: acid value of max. 2, iodine value of max. 2, saponification value of 79-93, hydroxyl value of 36-56, peroxide value of max. 6, alkaline impurities max. 80, max. water content 0.50, free glycerol content max. 3, monoglyceride content 3.0-8.0. (H. Fiedler, loc. Cit., Vol 1, page 676; manufacturer information).

11) Polyethylene glycol glyceryl fatty acid esters

[0114] The fatty acid ester may include mono and / or di and / or tri fatty acid ester. The fatty acid constituent may include saturated and unsaturated fatty acids having a chain length of for example C12-C18. The polyethylene glycols can have for example 10 to 40 units [CH2-CH2-O], for example 15 or 30 units. Particularly suitable is polyethylene glycol glyceryl monostearate (15) which is commercially available, for example under the trade name TGMS®-15, for example from Nikko Chemicals Co., Ltd. Other suitable glyceryl fatty acid esters include polyethylene glycol glyceryl mooletate (30) which it is commercially available, for example under the trade name Tagat® O, for example from Goldschmidt (H. Fiedler, loc. cit., vol. 2, p. 1502-1503), and Tagat 02 (glycerol olyethylene glycol monoleate (20), as well as Tagat L (glycerol polytethylene glycol monolaurate (30)) and Tagat L2 (polytethylene glycol glyceryl monolaurate (20)), all for example from Goldschmidt (H. Fiedler, loc. cit., vol. 2, p. 1502-1503) An additional suitable polyethylene glycol glyceryl fatty acid ester is Tagat TO.

12) Sterols and their derivatives

[0115] These include cholesterols and their derivatives, in particular phytosterols, for example products comprising sitosterol, campesterol or stigmasterol, and their ethylene oxide adducts, for example soy sterols and their derivatives, for example polyethylene glycol sterols, for example phytosterols polyethylene glycol or soy sterols polyethylene glycol. The polyethylene glycols can have for example 10 to 40 units [CH2-CH2-O], for example 25 or 30 units. Particularly suitable is phytosterol polyethylene glycol (30) which is commercially available, for example under the trade name Nikkol BPS®-30, for example from Nikko Chemicals Co., Ltd. The additional suitable polyethylene glycol soybean (25) is commercially available, by example under the trade name General® 122 E 25, for example Henkel (H. Fiedler, loc. cit., vol. 1, p. 680).

13) Transesterified polyoxylated caprylic acid-capsid glycerides

[0116] These include those that are commercially available under the trade name Labrasol® of for example Gattefossé. Labrasol® has an acid value of max. 1, a saponification value of 90-110, and an iodine value of max. 1 (H. Fiedler, loc. Cit., Vol 2, page 880).

14) Sugar fatty acid esters

[0117] These include those of C12-C18 fatty acids, for example sucrose monolaurate, for example Ryoto L-1695®, which is commercially available from for example Mitsubishi-Kasei Food Corp., Tokyo, Japan.

15) PEG sterol ethers

[0118] These include those that have, for example, 5 to 35 units [CH2-CH2-O], for example 20 to 30 units, for example Solulan® C24, which is commercially available from, for example, Amerchol.

16) Dioctylsodiosulfosuccinate

[0119] This is commercially available under the Aerosol OT® trademark of for example American Cyanamid Co. (Fiedler, loc. Cit., 1, p. 118), or di- [2-ethylhexyl] -succinate (Fiedler, loc cit., volume 1, p. 487).

17) Phospholipids

[0120] These include in particular lecithins (Fiedler, loc. Cit., Volume 2, p. 910, 1184). Suitable lecithins include, in particular, soybean lecithins.

18) Salts of fatty acids, sulfates and fatty acid sulphonates

[0121] These include those of for example C6-C18, fatty acids, sulfates and fatty acid sulphonates, as is known and commercially available from for example Fluka.

19) Acylated amino acid salts

[0122] These include those of C6-C18, acylated amino acids, for example sodium lauryl sarcosinate, which is commercially available from for example Fluka.

20) Medium or long chain alkyl, for example C6-C18 ammonium salts

[0123] These include C6-C18 acylated amino acids for example cetyl trimethyl ammonium chromite, which is commercially available from for example E. Merck AG.

[0124] The surfactant may comprise 5 to 90% by weight of the composition of the invention; preferably 15 to 85% by weight, more preferably 20 to 60% by weight and even more preferably between about 35% and about 55% by weight.

[0125] Certain embodiments of the compositions of the invention include additives for example antioxidants, antimicrobial agents, enzyme inhibitors, stabilizers, preservatives, flavorings, sweeteners and other components such as those described in Fiedler, H. P., loc. cit.

[0126] Preferred antioxidants include ascorbyl palmitate, butyl hydroxy anisole (BHA), butyl hydroxy toluene (BHT) and tocopherols. The antioxidant αtocopherol (vitamin E) is especially preferred.

[0127] These additives or ingredients may comprise approximately 0.05 to 5% by weight of the total weight of the composition. Antioxidants, antimicrobial agents, enzyme inhibitors, stabilizers or preservatives typically provide up to about 0.05 to 1% by weight based on the total weight of the composition. Sweetening or flavoring agents typically provide up to about 2.5 or 5% by weight based on the total weight of the composition.

[0128] The additives mentioned above may also include components that ground a liquid microemulsion preconcentrate (MEPC). These include solid polyethylene glycols (PEGs) and Gelucire ™ products, preferably those such as Gelucire ™ 44/14 or Gelucire ™ 50/13 that function as additional surfactants.

[0129] In a seventh aspect the invention provides a process for preparing a spontaneously dispersible pharmaceutical composition containing a 5-aryl-4 (R) -arylcarbonylamino-pent-2-enoic acid amide substance P antagonist as an active agent. , which process comprises bringing the active agent and a carrier medium comprising (1) a lipophilic component, (2) a surfactant, and optionally (3) an intimate mixture hydrophilic component.

[0130] The carrier medium can be prepared separately before bringing the active agent in intimate mixing with the carrier medium. Alternatively two or more of the components of the carrier medium can be mixed together with the active agent. [0131] The spontaneously dispersible pharmaceutical composition is preferably a microemulsion preconcentrate as defined herein. [0132] The spontaneously dispersible pharmaceutical composition preferably spontaneously or substantially spontaneously forms an emulsion o / w (oil in water), for example microemulsion, when diluted with an aqueous medium such as water in a dilution of 1: 1 to 1: 300 , for example 1: 1 to 1:70, especially 1:10 to 1:70, more especially for example 1:10, or in the gastric juices of a patient after oral application. [0133] In an eighth aspect the invention provides a process for preparing a microemulsion containing a 5-aryl-4 (R) arylcarbonylamino-pent-2-enoic acid amide substance P antagonist as an active agent, the process of which comprises :

(i) bringing the active agent and a carrier comprising (1) a lipophilic component,

(2)

a surfactant, and optionally (3) a hydrophilic component in intimate mixture to form a spontaneously dispersible pharmaceutical composition; Y

(ii)

dilute the pharmaceutical composition spontaneously dispersible in an aqueous medium to form the microemulsion. [0134] As mentioned above, the active agent may be present in a

amount by weight of up to about 20% by weight of the composition of the invention, for example about 0.05% by weight. The active agent is preferably present in an amount of 0.5 to 15% by weight of the composition, more preferably in an amount of 1.5 to 5% by weight of the composition.

[0135] The lipophilic component preferably comprises 5 to 85% by weight of the composition of the invention, for example 10 to 85%; preferably 15 to 60% by weight, more preferably about 20 to about 40% by weight.

[0136] The hydrophilic component (when present) may comprise 5 to 60% by weight of the composition of the invention, for example 10 to 50%; preferably 10 to 40% by weight, more preferably about 10 to about 30% by weight. This may comprise a mixture of two or more hydrophilic components. The ratio of the main hydrophilic component to the hydrophilic cocomponent is typically from about 0.5: 1 to about 2: 1.

[0137] The surfactant may comprise 5 to 90% by weight of the composition of the invention; preferably 15 to 85% by weight, more preferably 20 to 60% by weight and even more preferably between about 35% and about 55% by weight.

[0138] The relative proportion of the active agent, the lipophilic component, the surfactant and the hydrophilic component (when present) are preferably within the "Microemulsion" region in a standard three-way plot. The compositions will therefore be of high stability which are capable, in addition to an aqueous medium, of providing microemulsions, for example they have an average particle size of <200 nm.

[0139] When the composition of the invention is a microemulsion preconcentrate it can be combined with water or an aqueous solvent medium to obtain an emulsion, for example a microemulsion. The emulsion or microemulsion can be administered enterically, for example orally, for example in the form of a drinkable solution.

[0140] When the composition of the invention is a preconcentrate of a unit microemulsion dosage of the microemulsion preconcentrate which is preferably used to fill orally administrable capsules. The capsules can be hard or soft capsules, for example made of gelatin. Each unit dosage will suitably contain 0.1 to 100 mg of active agent, for example 0.1 mg, 10 mg, 15 mg, 25 mg or 50 mg, preferably between 10 and 100 mg of the active agent, more preferably between 10 and 50 mg; for example 15, 20, 25, or 50 mg, more preferably between 5 and 20 mg, more preferably 5 or 10 mg. Such unit dosage forms are suitable for administration 1 to 5 times daily depending on the particular purpose of therapy, the phase of therapy and the like. However, if desired, the compositions may be in a form of drinkable solution and may include water or any other aqueous system, for example fruit juice, milk, and the like, to provide for example colloidal systems, suitable for drinking, for example. example with a dilution of about 1:10 to about 1: 100.

[0141] The compositions of the invention, for example those in the examples hereinafter, may show good stability characteristics as indicated by standard stability tests, for example that have a shelf life stability of up to one, two or three years. , and even more. A group of compositions of the invention can be of high stability since they are capable, in addition to water, of providing aqueous microemulsions having an average particle size of <200 nm (2,000 Å), for example <150 nm (1,500 Å ), for example <100 nm (1,000 Å).

[0142] The compositions of the invention exhibit especially advantageous properties when administered orally; for example in terms of consistency and high level of bioavailability obtained in standard bioavailability tests.

[0143] Pharmacokinetic parameters, for example drug substance absorption and measurement such as blood levels, also become surprisingly more predictable and problems in administration with erratic absorption can be eliminated or reduced. Additionally the pharmaceutical compositions are effective with biotensoactives or surfactant materials, for example bile salts, which are present in the gastro-intestinal tract. That is, the pharmaceutical compositions of the present invention are fully dispersible in aqueous systems comprising such natural surfactants and thus are capable of providing emulsion or microemulsion systems and / or in situ particulate systems that are stable. The role of pharmaceutical compositions after oral administration remains substantially independent of and / or not impaired through the presence or relative absence of bile salts at any particular time or for any given individual. The compositions of this invention can also reduce variability in inter-and intra-patient dose response.

[0144] The utility of the compositions of the invention can be observed in standard clinical tests in, for example, known indications of the active agent in dosages that give blood levels of therapeutically effective active agent. Any increased bioavailability of the compositions of the invention can be observed in standard animal tests and in clinical trials.

[0145] The dose of the active agent in the compositions of the invention is in the same order as, or up to half, of what is used in known compositions containing the active agent. The compositions of the invention show activity in concentrations of about 0.1 mg to about 40 mg / day of the active agent, preferably about 0.1 mg to about 20 mg / day, for example more preferably about 0.1 to about 1 mg / day of agent active for respiratory disease states.

[0146] The compositions of the invention are useful for the treatment of respiratory diseases, for example asthma and chronic bronchitis. For these indications, the appropriate dosage, of course, will vary depending on, for example, the particular composition of the invention employed, the host, the mode of administration, and the nature and severity of the conditions to be treated.

[0147] A typical dose for the active agent is 0.1 to 1 mg / day for asthma and chronic bronchitis.

[0148] The invention is illustrated by the following Examples.

EXAMPLES

[0149] In the following examples the pharmaceutically active agent is Compound A ie N - [(R) -epsilon-caprolactam-3-yl] -amide (4R) -4- [N'-methyl-N ' - (3,5-bistrifluoro-methyl

benzoyl) amino] -4- (3,4-dichlorobenzyl) -but-2-enoic.

Example 1

Full capsule (or oral solution)

[0150] The formulation contains:

Compound A

20 mg

Cremofor RH 40

215 mg

Mono- / diglyceride C8 / C10

130 mg

Triethyl citrate

85 mg

Ethanol

50 mg

Example 2

Stuffed capsule (or oral solution)

[0151] The formulation contains:

Compound A

10 mg

Cremofor RH 40

219 mg

Corn Oil Glycerides

174 mg

Propylene glycol

27 mg

Ethanol

75 mg

Tocopherol

0.5 mg

Example 3

Oral solution

[0152] The formulation contains:

Compound A

10 mg / ml

Cremofor RH 40

439 mg

Corn Oil Glycerides

343 mg

Propylene glycol

88 mg

Ethanol

99 mg

Tocopherol

1.0 mg

[0153] The compositions of all three examples are prepared whereby carrier components are mixed and the active ingredient is dissolved there while stirring. Hard gelatin capsules are filled with the formulation mixtures of Examples 1 and 2 and sealed using the Quali-Seal ™ sealing technique.

[0154] Similarly, additional examples are prepared as follows:

Excipients

mg / 1g

Cremofor RH40

423

Corn Oil Glycerides

253.8

PEG400

169.2

Ethanol

94

Compound A

60

Cremofor RH40

423

Corn Oil Glycerides

253.8

Triethyl citrate

169.2

Ethanol

94

Compound A

60

Cremofor RH40

418.5

C8 / C10 mono- / diglycerides

251.1

PEG400

167.4

Ethanol

93

Compound A

70

Cremofor RH40

400.5

C8 / C10 mono- / diglycerides

240.3

Propylene glycol

160.2

Ethanol

89

Compound A

110

Cremofor RH40

480

C8 / C10 mono- / diglycerides

288

Triethyl citrate

192

Compound A

40

PEG-20 glyceryl oleate

380

C8 / C10 mono- / diglycerides

285

Triethyl citrate

190

Ethanol

95

Compound A

fifty

Cremofor RH40

432

Propylene Glycol Monocrapilate

345.6

Span 80

86.4

Triethyl citrate

96

Compound A

40

Cremofor RH40

405

C8 / C10 mono- / diglycerides

180

Propylene Glycol Monocrapilate

180

Ethanol

135

Compound A

100

Cremofor RH40

405

C8 / C10 mono- / diglycerides

180

Propylene Glycol Monocrapilate

90

Triethyl citrate

90

Ethanol

135

Cremofor EL 480 Capriol 90 288 5 Triethylcitrate 192

Compound A 40 [0155] No separation or precipitation phase is observed for any of the above compositions that are clear for at least 4 hours.

2. Bioavailability

[0156] The bioavailability analysis of Example 1 in a dog study shows that single peroral doses of 20 mg of Compound A gives a standard capsule formulation using micronized DS (formulation A) resulting in significantly lower plasma levels of the Compound A (∼50%) which gives as microemulsion (formulation B). For illustration of the data see the table and figure below.

15 [0157] Form A: Capsule powder, Form B: Microemulsion

image 1

3. Embodiment: [0158] In general for our microemulsions the most preferred embodiment are soft gelatin capsules. This is due to the fact that the number of microemulsion excipients per

For example, propylene glycol, are incompatible with hard gelatin capsules that make them fragile. Soft gelatin capsules contain a large amount of fabric softener and therefore compatibility is better.

Claims (14)

25 CLAIMS

one.

A spontaneously dispersible pharmaceutical composition comprising a 5-aryl-4 (R) -arylcarbonylamino-pent-2enoic acid amide substance P antagonist and a carrier medium comprising a lipophilic component and a surfactant.

2.

A spontaneously dispersible pharmaceutical composition as claimed in claim 1, wherein the carrier medium further comprises a hydrophilic component.

3.

A pharmaceutical composition as claimed in claim 1 or 2 wherein the 5-aryl-4 (R) -arylcarbonylamino-pent-2enoic acid amide substance P antagonist is N - [(R) -epsilon-caprolactam-3 -yl] -amide of (4R) -4- [N'-methyl-N '- (3,5-bistrifluoro-methyl-benzoyl) amino] -4- (3,4-dichlorobenzyl) -but-2-enoic acid.

Four.

A pharmaceutical composition comprising N - [(R) -epsilon-caprolactam-3-yl] amide (4R) -4- [N'-methyl-N '- (3,5-bistrifluoromethyl-benzoyl) aminol-4 - (3,4-dichlorobenzyl) -but-2-enoic as an active agent and a carrier medium comprising a lipophilic component, a surfactant and optionally a hydrophilic component, said composition is in a form that is suitable for oral administration.

5.

A composition as claimed in claim 1 or 4 wherein the lipophilic component comprises C8-C10 fatty acid monoglycerides and diglycerides or a corn oil transesterified with refined glycerol.

6.

A composition as claimed in any one of claims 2, 4 and 5 wherein the hydrophilic component comprises propylene glycol.

7.

A composition as claimed in any one of claims 1, 4, 5 and 6 wherein the surfactant comprises a hydrogenated polyethylene glycol castor oil.

8.

A spontaneously dispersible pharmaceutical composition comprising about 0.05 to about 20% by weight of (4R) -4- [N'-methyl-N '- (3, N-[(R) epsiloncaprolactam-3-yl] -amide) 5-bistrifluoro-methylbenzoyl) amino] -4- (3,4-dichlorobenzyl) -but-2-enoic, about 5 to about 85% by weight of a lipophilic component, about 5 to about 90% by weight of a surfactant, and optionally about 5 to about 60% by weight of a hydrophilic component, all weights based on the total composition.

9.

A composition as claimed in any one of claims 1 to 8 in the form of a microemulsion preconcentrate.

10.

A composition as claimed in any one of claims 1 to 8 in the form of a microemulsion.

eleven.

A composition according to any preceding claim in unit dosage form.

12.

A composition according to claim 11 in encapsulated form of hard or soft gelatin.

13.

A process for preparing a spontaneously dispersible pharmaceutical composition containing a 5-aryl-4 (R) arylcarbonylamino-pent-2-enoic acid amide substance antagonist as an active agent, the process of which comprises bringing the active agent and a medium carrier comprising (1) a lipophilic component, (2) a surfactant, and optionally (3) a hydrophilic component in intimate mixing.

14.

A process for preparing a microemulsion containing a 5-aryl-4 (R) -arylcarbonylamino-pent-2-enoic acid amide substance P antagonist as an active agent, the process of which comprises:

(i)

bringing the active agent and a carrier comprising (1) a lipophilic component, (2) a surfactant, and optionally (3) an intimate mixture hydrophilic component to form a spontaneously dispersible pharmaceutical composition; Y

(ii)

dilute the pharmaceutical composition spontaneously dispersible in an aqueous medium to form the microemulsion.